AB0017 HOW DO B CELLS EVADE RITUXIMAB THERAPY IN AUTOIMMUNITY; IS IT TIME TO TARGET THE CD19+CD20- B CELLS?
Authors: K. Shah, C. Klein, G. Cambridge, D. Sen, M. Castelino, A. Akbar, D. Isenberg, M. J. Leandro, V. Reddy
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Following treatment of autoimmune disease with anti-CD20 monoclonal antibody, Rituximab, insufficient B cell depletion relates to poor clinical response, in particular an expansion of memory B cells [1]. <h3>Objectives</h3> We investigated whether the relative expression of the target antigen CD20 on B cell subpopulations underlies drug resistance. <h3>Methods</h3> Peripheral blood samples from 6 rituximab naïve (RTX-N) patients with autoimmune rheumatic diseases (active systemic lupus erythematosus) and rheumatoid arthritis), 6 patients previously treated with rituximab (RTX-T); and 6 healthy controls (HC) were obtained. B cell subpopulations were defined using the relative expression of IgD and CD27 using flow cytometry. <h3>Results</h3> Patients in the RTX-N group had significantly higher frequency of CD19+CD20-B cells (median=25.9% of total B cell, compared to 1.26% in HC), p =0.0022. CD19+CD20-B cells were predominantly swMBC and DN cells. All patients in the RTX-T group (median 22 months post rituximab) had detectable CD19+CD20-B cells (median=52.25 % of total B cells), of which the majority were swMBC (median=4.54%, range 0.23-74%) and DN B cells (median=53.5%, range 11.6-98.1%). Collectively, we noted that the median frequency of CD19+CD20-B cells in peripheral circulation was higher in RTX-T &gt; RTX-N &gt; HC. <h3>Conclusion</h3> Our preliminary results have identified greater frequency of CD19+CD20- population of B cells in peripheral blood of patients with autoimmune disease, particularly after treatment with rituximab suggesting that they evade rituximab. These are predominantly of the switched MBC and DN B cell subpopulations. Given, the potential of these cells to contribute to disease activity in autoimmune disease, is it now time to seek alternative strategies targeting CD19 in order to overcome rituximab resistance? <h3>Reference</h3> [1]Vital, E.M., et al., <i>B cell biomarkers of rituximab responses in systemic lupus erythematosus.</i> Arthritis Rheum, 2011. <b>63</b>(10): p. 3038-47. Figure above demonstrates the cycle of B lineage cells which originate in the bone marrow and migrate into the peripheral circulation and into lymphoid tissues such as lymph nodes and the spleen. In germinal centres the naïve B cells mature into memory B cells which then differentiate into tissue resident switched memory B cells (CD27+, IgD-), or double negative memory B cells entering the peripheral circulation (CD27-, IgD-) or plasma blasts and plasma cells of which the long-lived ones reside in the bone marrow. Proportions of CD19+CD20+ v CD19+CD20- B cells are demonstrated pictorially within each subpopulation. The CD19+CD20- B cells cannot be targeted by anti-CD20 monoclonal antibodies such as rituximab, and therefore alternative strategies to target CD19 may help to overcome rituximab resistance in autoimmunity. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Kavina Shah Grant/research support from: Roche Glycart, Christian Klein Shareholder of: Roche, Employee of: Roche Glycart, Geraldine Cambridge: None declared, Debajit Sen: None declared, Madhura Castelino: None declared, Arne Akbar: None declared, David Isenberg: None declared, Maria José Leandro: None declared, Venkat Reddy: None declared.